During the development of a commercially viable asymmetric synthesis of a potent endothelin antagonist, a highly stereoselective synthesis of a key intermediate, a 2-aryloxycarboxylic acid needed to be developed. A variety of methods of general applicability have been worked out by Durst and Koh utilizing (R)-pantolactone as a chiral auxiliary. See Koh, K.; Durst, T. J. Org. Chem. 1994, 59, 4683.! Pantolactone esters of racemic .alpha.-halo acids have been coupled to a variety of phenoxides. Diastereoselectivities ranging from 76-90% have been obtained in this fashion with the "S" stereochemistry predominating at the newly formed asymmetric center. The "R" stereochemistry can be obtained utilizing (S)-ethyl lactate as the chiral auxiliary although diastereoselectivities are significantly lowered in comparison to pantolactone (60-75%). For other diastereoselective reactions utilizing pantolactone or ethyl lactate see: (a) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111, 7650. (b) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1994, 35, 375. (c) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1993, 34, 4473.! The reaction is also characterized by sluggish rates and moderate yields.
The instant invention relates to a highly stereoselective coupling reaction mediated with a pyrrolidine derived lactamide as a chiral auxiliary.